Fiche publication
Date publication
octobre 2015
Journal
Bioconjugate chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr VALVERDE Ibai
Tous les auteurs :
Mascarin A, Valverde IE, Vomstein S, Mindt TL
Lien Pubmed
Résumé
Neurotensin (NT) is a regulatory peptide with nanomolar affinity toward NT receptors, which are overexpressed by different clinically relevant tumors. Its binding sequence, NT(8-13), represents a promising vector for the development of peptidic radiotracers for tumor imaging and therapy. The main drawback of the peptide is its short biological half-life due to rapid proteolysis in vivo. Herein, we present an innovative strategy for the stabilization of peptides using nonhydrolizable 1,4-disubstituted, 1,2,3-triazoles as amide bond surrogates. A "triazole scan" of the peptide sequence yielded novel NT(8-13) analogues with enhanced stability, retained receptor affinity, and improved tumor targeting properties in vivo. The synthesis of libraries of triazole-based peptidomimetics was achieved efficiently on solid support by a combination of Fmoc-peptide chemistry, diazo transfer reactions, and the Cu(I)-catalyzed alkyne azide cycloaddition (CuAAC) employing methods that are fully compatible with standard solid phase peptide synthesis (SPPS) chemistry. Thus, the amide-to-triazole substitution strategy may represent a general methodology for the metabolic stabilization of biologically active peptides.
Mots clés
Animals, Antineoplastic Agents, chemistry, Chemistry Techniques, Synthetic, Cycloaddition Reaction, Female, HT29 Cells, Half-Life, Humans, Isotope Labeling, methods, Lutetium, chemistry, Mice, Nude, Molecular Targeted Therapy, methods, Neurotensin, chemistry, Peptide Fragments, chemistry, Peptidomimetics, chemistry, Radioisotopes, chemistry, Receptors, Neurotensin, metabolism, Structure-Activity Relationship, Tissue Distribution, Triazoles, chemistry, Xenograft Model Antitumor Assays
Référence
Bioconjug. Chem.. 2015 Oct 21;26(10):2143-52
